The Role of Bone Marrow in the Immune Response

Abstract Dendritic cells (DCs) along with mast cells function as sentinels for the innate immune system and perform as antigen presenting cells (APCs) to mount an adaptive immune response against invading pathogen. FLT3 receptor tyrosine kinase signaling has been shown to regulate the homeostatic mechanisms of subsets of DCs particularly, CD103+DCs compared to CD11b+DCs. CD103+DCs are regarded as APCs with superior capabilities to mount an effective immune response, thus understanding their homeostasis mechanism(s)/function is of paramount importance to devise effective therapeutics including DC vaccines. The Src-like adapter protein (SLAP) has been shown to dampen the signaling downstream of receptor tyrosine kinases including FLT3, cKit, and immune cell receptors including T cell receptor, B cell receptor, and Granulocyte-monocyte colony stimulating factor receptor via by recruiting c-Cbl, an ubiquitin ligase. Here, we report that SLAP deficient mice (KO) have reduced numbers of CD103+DC in lung while equal numbers in liver and kidney compared to control mice. To further confirm reduced CD103+DC in the lung, efferocytosis assays that are dependent upon CD+103 DC in lung epithelium to cleanse the apoptotic cells were performed. Flow cytometric quantification of CD103+DCs that uptake fluorescently labeled apoptotic cells administered via intranasal route and migrate to mediastinal lymph nodes confirmed reduced number of CD103+DCs in SLAP KO mice. Further analysis of DC progenitor populations showed reduced pre-DC progenitor in the lung in SLAP KO mice while bone marrow compartment showed equal progenitor populations including pre-DC and common dendritic progenitors suggesting the role of SLAP in localized FLT3 signaling in the lung. Consistently, DCs in lymphoid compartment including spleen, thymus, inguinal and popliteal lymph node did not show any defects. Upon further dissecting the cellular mechanism, SLAP KO DCs showed increased apoptosis while having similar proliferation potential in vivo at steady state.Bone marrow progenitors from SLAP KO mice failed to generate mature DCs in the presence of FLT3 ligand in vitrodue to enhanced apoptosis at early time points. Also, submaximal inhibition of FLT3 with an inhibitor, quizartinib partially rescues the apoptotic phenotype of SLAP KO bone marrow progenitors suggesting a cell-intrinsic role of SLAP in the survival of DCs. Biochemical analysis revealed that SLAP is directly recruited to the juxta-membrane residues of the FLT3 receptor in an inducible manner suggesting a direct role of SLAP in the regulation of FLT3 signaling. Phosphoflow analysis of DCs generated in the combined presence of GMCSF and FLT3 ligands showed that SLAP promotes the signaling to SHP2 while perturbs signaling to the mTOR pathway. Together these results suggest that SLAP is a critical regulator of CD103+DCs homeostasis in selective peripheral organs including the lung. Disclosures No relevant conflicts of interest to declare.

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Role of the Thrombin-PAR-1 Pathway in Coxsackievirus Induced Hepatitis

Blood ◽

10.1182/blood.v124.21.1470.1470 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1470-1470

Author(s):

Kohei Tatsumi ◽

Silvio Antoniak ◽

Nigel Mackman

Keyword(s):

Bone Marrow ◽

Immune Response ◽

Innate Immune Response ◽

Innate Immune ◽

Primary Mouse Hepatocytes ◽

Primary Mouse ◽

Mouse Hepatocytes ◽

Transplantation Experiments

Abstract Objective: Coxsackievirus B3 (CVB3) can infect different tissues including the heart and liver. Recently, we found that activation of the coagulation cascade and protease-activated receptor 1 (PAR-1) enhances toll-like receptor-3 (TLR3) mediated interferon-β (IFN-β) expression and protects mice from CVB3-induced myocarditis. Here, we investigated the role of PAR-1 in early anti-viral responses in mice and isolated hepatocytes. Methods: Wild-type (WT) and PAR-1 deficient (PAR-1-/-) mice were infected with CVB3 intraperitoneally. The innate immune response, viral load, liver enzyme plasma levels, and inflammation levels were analyzed. Bone-marrow transplantation experiments with the combination of WT mice PAR-1-/- mice were performed to identify the cellular source of PAR-1 contributing to the innate immune response to CVB3. We also analyzed the effect of the direct thrombin inhibition with dabigatran etexilate on CVB3 hepatitis. In addition, we analyzed the effect of PAR-1 activation on TLR3-dependent interferon (IFN)-β expression in primary mouse hepatocytes and the human hepatocyte cell line PH5CH8 in vitro. Results: PAR-1-/- mice exhibited a reduced early innate immune response in the liver at day 4 after infection, which was associated at later times (day 8) to higher viral titers in the liver, increased alanine transaminase plasma levels and more remarkable inflammation compared to control WT mice. Bone marrow transplantation experiments demonstrated that PAR-1 on non-hematopoietic played the major role in the innate immune response of CVB3 hepatitis. Stimulation of PAR-1 with either thrombin or agonist peptide on primary mouse hepatocytes and human PH5CH8 cells in vitro enhanced the antiviral response to dsRNA by increasing IFN-β and C-X-C motif chemokine 10 (CXCL10) expressions, supporting the results of in vivo experiments. Conclusion: Our results suggest that activation of PAR-1 on hepatocytes enhances the innate immune response to CVB3 in the liver. Disclosures No relevant conflicts of interest to declare.

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Toll like Receptor 2 Signaling Regulates Hematopoietic Stem Cell Function and Promotes G-CSF Mediated HSC Mobilization

Blood ◽

10.1182/blood.v124.21.4334.4334 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4334-4334

Author(s):

Angela Herman ◽

Molly Romine ◽

Darlene Monlish ◽

Laura G. Schuettpelz

Keyword(s):

Bone Marrow ◽

Immune Response ◽

Stem Cell ◽

Hematopoietic Stem Cell ◽

Immune Cell ◽

Conflicts Of Interest ◽

Wild Type ◽

Hematopoietic Stem ◽

Tlr2 Signaling

Abstract Toll like receptors (TLRs) are a family of pattern recognition receptors that play a central role in pathogen recognition and shaping the innate immune response. While most of the studies of the role of TLRs have focused on mature immune cell populations, recent reports suggest that TLR signaling may regulate the immune response from the level of the hematopoietic stem cell (HSC). In this study, we sought to further elucidate the effects of systemic TLR ligand exposure on HSCs and determine the cell-intrinsic versus extrinsic effects of such exposure. We specifically focused on TLR2 signaling, as although TLR2 is expressed on HSCs, it’s role in their regulation is not clear. Furthermore, enhanced TLR2 signaling is associated with myelodysplastic syndrome (Wei et al, Leukemia 2013), suggesting that aberrant signaling through this receptor may have clinically significant effects on HSC function. To elucidate the role of TLR2 signaling in regulating HSCs, we used mice with genetic loss of TLR2, as well as a synthetic agonist of TLR2 (PAM3CSK4) to determine the effects of TLR2 signaling loss or gain, respectively, on HSC cycling, mobilization and function. While TLR2 expression is not required for normal HSC function, treatment of wild-type mice with PAM3CSK4 leads to expansion of HSCs in the bone marrow and spleen, increased HSC cycling, and loss of HSC function in competitive bone marrow transplantation experiments. As TLR2 is expressed on a variety of stromal and hematopoietic cell types, we used bone marrow chimeras (Tlr2-/- + Tlr2+/+ marrow transplanted into Tlr2+/+ recipients) to determine if the effects of PAM3CSK4 treatment are cell intrinsic or extrinsic. The data suggests that HSC cycling and expansion in the marrow and spleen upon PAM3CSK4 treatment are extrinsic (occurring in both transplanted HSC populations), and are associated with increased serum levels of G-CSF. Indeed, inhibition of G-CSF using either a neutralizing antibody or mice lacking the G-CSF receptor (Csf3r-/-) leads to even further enhanced HSC bone marrow expansion upon G-CSF treatment but significantly reduced numbers of spleen HSCs compared to similarly treated wild-type mice. This suggests mobilization in response to TLR2 signaling is an indirect, G-CSF-mediated process. Ongoing studies are aimed at determining the contribution of G-CSF to the PAM3CSK4- induced loss of HSC function, and determining the source (stromal vs hematopoietic) of G-CSF production upon PAM3CSK4 exposure. Collectively, this data suggest that TLR2 signaling affects HSCs in a largely extrinsic fashion, with G-CSF playing a major role in regulating the effects of TLR2 ligand exposure on HSCs. Disclosures No relevant conflicts of interest to declare.

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Radiation leukemia in C57BL/6 mice. I. Lack of serological evidence for the role of endogenous ecotropic viruses in pathogenesis.

Journal of Experimental Medicine ◽

10.1084/jem.144.6.1391 ◽

1976 ◽

Vol 144 (6) ◽

pp. 1391-1405 ◽

Cited By ~ 33

Author(s):

J N Ihle ◽

R McEwan ◽

K Bengali

Keyword(s):

Bone Marrow ◽

Immune Response ◽

Humoral Immune Response ◽

Experimental Conditions ◽

Humoral Immune ◽

Apparent Correlation ◽

Radiation Induced ◽

Leukemia Viruses ◽

And Control

The humoral immune response against endogenous ecotropic murine leukemia viruses (MuLV) was examined in irradiated and control C57BL/6 mice. Control mice developed antibodies against MuLV slowly throughout life. In contrast, within 2-3 mo after irradiation 90% of irradiated C57BL/6 mice had developed detectable antibodies against MuLV. The characteristics of this immune response, however, were identical in control and irradiated mice in terms of peak titers, specificity for endogenous ecotropic MuLV, and reactivity against the ecotropic viruses' glycoprotein (gp71). Moreover, the rate of appearance of antibodies against MuLV in irradiated mice and the peak titers were generally not affected by age at irradiation, dose of irradiation (two, three, or four treatments of 175 R), or bone marrow reconstitution. Although the ability of irradiation to accelerate the appearance of antibody in a population of C57BL/6 mice suggested activation of endogenous ecotropic MuLV, there was no apparent correlation between the appearance of this immune response or its persistence and the development of lymphoma. Thus, the incidence of lymphoma was comparable in mice that: (a) developed no immune response; (b) developed an immune response only transiently after irradiation; or (c) developed an immune response which persisted until death from lymphoma. Moreover, experimental conditions that alter the ability of irradiation to induce leukemia, such as age, dose, or bone marrow reconstitution did so without significantly altering either the rate of appearance of a humoral immune response to MuLV or its peak titers. The results, therefore, fail to demonstrate any seroepidemological relationship between endogenous ecotropic MuLV and radiation-induced leukemia.

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CD8+γδ T Cells Are More Frequent in CMV Seropositive Bone Marrow Grafts and Display Phenotype of an Adaptive Immune Response

Stem Cells International ◽

10.1155/2019/6348060 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Ahmed Gaballa ◽

Lucas C. M. Arruda ◽

Emelie Rådestad ◽

Michael Uhlin

Keyword(s):

Bone Marrow ◽

Immune Response ◽

T Cells ◽

T Cell ◽

Gene Segment ◽

Adaptive Immune Response ◽

T Cell Subsets ◽

Effector Memory ◽

Adaptive Immune

The role of gamma delta (γδ) T cells in human cytomegalovirus (HCMV) immune surveillance has been the focus of research interest for years. Recent reports have shown a substantial clonal proliferation of γδ T cells in response to HCMV, shedding light on the adaptive immune response of γδ T cells. Nevertheless, most efforts have focused on Vδ2negγδ T cell subset while less attention has been given to investigate other less common γδ T cell subsets. In this regard, a distinct subpopulation of γδ T cells that expresses the CD8 coreceptor (CD8+γδ T cells) has not been thoroughly explored. Whether it is implicated in HCMV response and its ability to generate adaptive response has not been thoroughly investigated. In this study, we combined flow cytometry and immune sequencing of the TCR γ-chain (TRG) to analyze in-depth bone marrow (BM) graft γδ T cells from CMV seropositive (CMV+) and CMV seronegative (CMV-) donors. We showed that the frequency of CD8+γδ T cells was significantly higher in CMV+ grafts compared to CMV- grafts (P<0.001). Further characterization revealed that CD8+γδ T cells from CMV+ grafts express Vγ9- and preferentially differentiated from a naive to terminal effector memory phenotype (CD27low/-CD45RO-). In line with these findings, TRG immune sequencing revealed clonal focusing and reduced usage of the Vγ9/JP gene segment in a CMV+ graft. Furthermore, CD8+γδ T cells showed an enhanced response to TCR/CD3 and cytokine stimulation in contrast to CD8-γδ T cells. We conclude that γδ T cells in BM grafts are reshaped by donor CMV serostatus and highlight the potential adaptive role of CD8+γδ T cells in HCMV immune response.

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The role of eosinophils in parasitism and allergies: A review.

Savannah Veterinary Journal ◽

10.36759/svj.2020.093 ◽

2020 ◽

pp. 36-44

Keyword(s):

Bone Marrow ◽

Immune Response ◽

Key Words ◽

Parasitic Infections ◽

Allergic Reactions ◽

Airway Remodelling ◽

Helminth Infections ◽

Research Findings ◽

Established Relationship

Eosinophils are bone marrow produced granulocytes known to play key roles in mammalian host’s defence against parasitic infections and allergic reactions. Although a lot of studies were carried out to establish these roles, conflicting research findings rendered the long-established relationship between eosinophils and the induction of allergic sensitivity and their roles in helminth infections controversial. Emerging evidence from recent research efforts showed that eosinophils stimulated airway remodelling and also served to control the immune response in allergic reactions. Research was conducted using databases such as Google, Google Scholar, Research gate, Scopus, Science Direct and Pub Med. The key words used for the search were eosinophils and eosinophilia, then the relevant articles were selected. This article explains the mechanism of eosinophilia in parasitism as well as allergic reactions. In this article, the concept of eosinophilia, its different classes and the role it plays in parasitism and allergies are reviewed and discussed.

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Bone Marrow Cell Rejection by Innate Immune Pathways Is Exclusively Dependent On the TRIF Pathway.

Blood ◽

10.1182/blood.v114.22.3526.3526 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3526-3526

Author(s):

Hong Xu ◽

Jun Yan ◽

Ziqiang Zhu ◽

Lala-Rukh Hussain ◽

Yiming Huang ◽

...

Keyword(s):

Bone Marrow ◽

Immune Response ◽

Innate Immunity ◽

Innate Immune Response ◽

Innate Immune ◽

Solid Organ ◽

Allogeneic Bone ◽

Wild Type ◽

Donor Chimerism

Abstract Abstract 3526 Poster Board III-463 Research on transplantation rejection, tolerance, and immunosuppressive agents has been directed toward the adaptive immune response as, until now, it has been believed to be the dominant mechanism for alloreactivity. The role of innate immunity in transplantation has not been fully defined. Despite the sentinel role of innate immunity in driving and shaping adaptive immunity, the contribution of innate immunity to bone narrow cells has only recently been identified. TLR4-driven MyD88-dependent immunity has been demonstrated to be critical for allogeneic innate immune responses to solid organ transplants. Whether innate immunity plays a role in BMC rejection has not been defined. In the present studies we tested whether the absence of MyD88 would enhance allogeneic engraftment in bone marrow transplantation (BMT). The core component of TLR signaling is activation of an IL-1-like pathway dependent upon the adapter MyD88. MyD88−/− B6 mice (n=6) were used to study the role of MyD88 signaling in allogeneic BMC rejection. As TRIF is another crucial adapter for TLR3 signaling and responsible for induction of signaling via type 1 IFNs, B6 TRIF−/− mice (n=6) were also investigated. Wild-type B6 (H2b, n=6) mice were used as controls. In the present study, MHC plus minor antigen-disparate BALB/c (H2d) mice served as allogeneic bone marrow donors. Recipients were nonmyeloablatively conditioned with anti-CD154 mAb (day0 and +3) to block CD40:CD154 co-stimulatory pathway and sirolimus (day0 to +4) to block late-stage T cell activation by inhibiting IL-2 responsiveness. Recipients were transplanted with 15 × 106 allogeneic (BALB/c; H2d) marrow cells 4-6 hours following conditioning with 100 cGy total body irradiation (TBI). Allogeneic engraftment was achieved in 33.3% of MyD88−/− recipients at 1 mo after BMT, a percentage similar to that for wild-type B6 mice. Surprisingly, 100% of TRIF−/− mice engrafted. The level of donor chimerism in TRIF−/− mice was 5.1 ± 0.6% at one month after BMT, which was significantly higher than in MyD88−/− (1.8 ± 1.0%; P < 0.0001) or in wild-type B6 mice (1.3 ± 0.8%; P < 0.005) and thereafter through all time points tested (2, 4 and 5 months, P < 0.05). The levels of donor chimerism increased with time and the level of donor chimerism reached 14.7 ± 7.1% TRIF−/− at five months. These results suggest that allogeneic BMC rejection is uniquely independent of the MyD88 pathway but rather involves TRIF signaling. These data suggest that the innate immune response to BMC differs from that for solid organs and may reflect the specificity of BMT compared with other transplants. These findings demonstrate for the first time that BMC elicit an innate immune response via the TRIF pathway and may open the door to novel approaches for immune-based conditioning to promote engraftment. Disclosures: Ildstad: Regenerex: Equity Ownership.

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Absolute Monocytosis At Diagnosis Is Associated with Poor Survival in Diffuse Large B-Cell Lymphoma -Possibly Related to Increase in Monocytic-Myeloid Derived Suppressor Cells

Blood ◽

10.1182/blood.v118.21.2641.2641 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2641-2641

Author(s):

Tamar Tadmor ◽

Rona Fell ◽

Aaron Polliack ◽

Dina Attias

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Immune Response ◽

Multivariate Analysis ◽

Prognostic Factors ◽

Peripheral Blood ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Poor Survival

Abstract Abstract 2641 Background: monocytes and macrophages play a role in promoting angiogenesis and suppression of the anti-tumor immune response. Monocytic-myeloid derived suppressor cells (M-MDSCs) are a subpopulation of immature myeloid cells which have immune-suppressive function and play a role in cancer tolerance. Some patients with malignant lymphoma exhibit peripheral blood monocytosis (PBM) at diagnosis but its exact prevalence is not known. Aim: Recently we encountered PBM in a few patients with DLBCL who had a rapidly progressive fatal course. This observation coupled with emerging data on the role of M-MDSCs is in the tumor microenvironment, led us to undertake a retrospective study to determine prevalence of PBM and its possible prognostic significance in DLBCL. In a proportion of these patients we also quantitated the M-MDSCs pool in the peripheral blood using flow cytometry in an attempt to assess possible changes in this subpopulation of monocytic cells in DLBCL. Material and methods: Clinical and laboratory data from medical records of 91 newly diagnosed patients with DLBCL seen at our institute during 1996–2010, were evaluated for the presence of absolute PBM> 1000 cells/mm3, at diagnosis and for possible correlations with other prognostic factors including age, stage, gender, B symptoms, extra nodal involvement, serum LDH and CRP levels, bone marrow (BM) involvement and IPI score. A Cox proportional hazards regression model was used to determine significance of the prognostic factors in a multivariate analysis. In the last 23 consecutive patients flow-cytometry analysis peripheral blood cells was also performed using surface staining for CD45+CD14+ HLA DR−/LOW to define the proportion of M-MDSCs compared to 15 healthy volunteers. Statistical analysis of was done using student T-TEST. Results: The median age of the entire patient cohort was 66 years (21–87); median follow up was 30 months: (1–332 months) and 57 % were men. All patients received CHOP or R-CHOP. PBM was found in 18.3% at diagnosis. In the multivariate analysis (Cox model), only PBM, bone marrow involvement and IPI score were found to be independent prognostic factors for overall survival (OS) while age and LDH weren't (Table). Blood samples collected at diagnosis from 23 patients showed increased numbers of M- MDSCs compared to healthy volunteers (9.59% range: 5.6–19 % and, 5.44% range 4.8–7.7 % respectively p<0.05).Levels of MDSCs decreased to within normal limits when performed 3 month following chemotherapy in patient in CR (5.76% range: 5.1–7.2 %). In conclusion: These results show that PBM is an independent factor for predicting poor survival in patients with DLCL and was as significant a risk factor as IPI score. This simple routine laboratory test can be utilized in daily practice as another indicator of poor outcome in DLBCL. The findings provide further support for the functional role of monocytes in the immune response in DLBCL. Furthermore, the consistent finding of significantly increased numbers of M-MDSC in the peripheral blood in these patients suggests that this subpopulation of immunosuppressive monocytes may contribute to the decreased tumor surveillance seen in DLBCL and may help to explain why absolute PBM is associated with poor outcome in these patients. Studies on their biological role as a marker of disease activity in DLBCL are in progress. Disclosures: No relevant conflicts of interest to declare.

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Cytokine regulation of the macrophage (M phi) system studied using the colony stimulating factor-1-deficient op/op mouse

Physiological Reviews ◽

10.1152/physrev.1996.76.4.927 ◽

1996 ◽

Vol 76 (4) ◽

pp. 927-947 ◽

Cited By ~ 101

Author(s):

W. Wiktor-Jedrzejczak ◽

S. Gordon

Keyword(s):

Bone Marrow ◽

Immune Response ◽

Dendritic Cells ◽

Growth Factors ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Local Populations ◽

Tissue Reactions ◽

Stimulating Factor

The macrophage (M phi) lineage is more complex than other myeloid lineages of hematopoietic cells and includes strikingly different end cells such as Kupffer cells, alveolar M phi, histiocytes, serosal M phi, synovial type A cells, microglia, osteoclasts, and possibly dendritic cells. These cells are formed under the influence of primary M phi growth factors such as colony stimulating factor (CSF)-1, granulocyte-M phi (GM)-CSF, and interleukin-3. The dissection of the system has been greatly facilitated by discovery of the osteopetrotic op/op mouse, which has a spontaneous knockout of the gene for CSF-1 and possesses generalized but differential deficiency of various local subpopulations of M phi. Studies using this model indicate that the M phi lineage is split into CSF-1-dependent and CSF-1-independent cells that are largely independently regulated. These contribute variably to different local populations and have largely, but not totally, overlapping functions. Both CSF-1 and GM-CSF are responsible for transition of cells of the M phi lineage from bone marrow to blood, and from blood to tissues, and have a critical extramedullary role. Regulation of the M phi system by CSF-1 is complex, with some local populations dependent on circulating CSF-1 and some supported exclusively by locally produced CSF-1. Colony stimulating factor-1-dependent M phi are not required for the generation of a specific immune response. Instead, most likely they play a regulatory role in various tissue reactions including responses to bacterial infection, neoplasia, and atherosclerosis. A hypothetical major role of CSF-1-independent M phi is to collaborate with lymphocytes in mounting an immune response. These issues need further exploration using animals with knockouts of genes for other M phi growth and activation factors and their receptors.

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Hepatitis B virus genomic nucleic acid in the activation and maturation of bone marrow-derived dendritic cells

Asia Pacific Journal of Molecular Biology and Biotechnology ◽

10.35118/apjmbb.2021.029.4.10 ◽

2021 ◽

pp. 109-119

Author(s):

Chean Ring Leong ◽

Tsukasa Seya ◽

Woei Yenn Tong ◽

Wen-Nee Tan

Keyword(s):

Bone Marrow ◽

Immune Response ◽

Hepatitis B Virus ◽

Nucleic Acid ◽

Hepatitis B ◽

Genomic Dna ◽

Innate Immune ◽

Adaptive Immune ◽

B Virus

Hepatitis B virus (HBV) is the etiological agent that causes a self-limiting or chronic infection in the hepatocytes of about 250 million people worldwide. The role of adaptive immune system during HBV infection has been well studied. However, the innate immune system's responses against HBV during the early stage of infection largely remain unclear. In this study, we found that HBV genomic DNA or Salmon Sperm DNA (SSD) was able to induce the innate immune response in the macrophages cell line RAW264.7 but not the hepatocyte cell line, HepG2, indicating that hepatocytes may lack of a functional DNA-sensing pathway and hence are unable to respond to the presence of foreign DNA in the cytosol with type 1 IFN response. Thus, we hypothesized that non-parenchymal cells like the Antigen Presenting Cells (APC) might be crucial in triggering the initial immune response to suppress the virus replication and link the innate and adaptive responses. Using bone marrow-derived DCs (BMDC) as a model, this study demonstrated that HBV genomic DNA is able to induce cytokines like TNF-alpha, IL-6, and IL-12p40 secretion. We also examined the activation and maturation of BMDCs when exposed to the HBV genomic DNA intracellularly and extracellularly. A significant shift of CD86+ and CD40+ cell populations was observed during extracellular exposure of BMDC to Poly I:C and HBV genomic DNA, indicating that TLRs may be vital in the uptake of the extracellular viral DNA to activate the BMDCs. Moreover, transfection of intracellular nucleic acid stimuli, including HBV genomic DNA as well induced BMDCs maturation. Our findings highlight the critical function of DCs in antiviral response as a potential connection between the innate and adaptive immune systems during HBV pathogenesis. Nevertheless, further study is required to determine the role of cytosol DNA sensing pathway in DCs during HBV infection.

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